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Natalia M. Moll, MD, PhD; Michael B. Cossoy, MD; Elizabeth Fisher, PhD; Susan M. Staugaitis, MD, PhD; Barbara H. Tucky, BS; Anna M. Rietsch, BS; Ansi Chang, MD; Robert J. Fox, MD; Bruce D. Trapp, PhD; Richard M. Ransohoff, MD

Arch Neurol. 2009;66(1):44-53.

Objective  To compare leukocyte accumulation and expression of the chemokine receptor/ligand pair CXCR4/CXCL12 in magnetic resonance imaging–defined regions of interest (ROIs) in brains from patients with chronic multiple sclerosis. We studied the following ROIs: normal-appearing white matter (NAWM); regions abnormal only on T2-weighted images (T2 only); and regions abnormal on T2- and T1-weighted images with an abnormal magnetization transfer ratio (T2/T1/MTR).

Design  Case-control study.

Setting  Cleveland Clinic.

Patients  Brain tissue was acquired from 5 patients with secondary progressive multiple sclerosis (MS) and 5 nonneurological controls.

Intervention  Magnetic resonance imaging pathological correlations were performed on the 5 cases. Based on imaging characteristics, 30 ROIs were excised.

Main Outcome Measure  Using immunohistochemical analysis, we evaluated myelin status, leukocyte accumulation, and CXCR4/CXCL12 expression in the MS ROIs and white matter regions from the 5 nonneurological controls.

Results  Eight of 10 T2/T1/MTR regions were chronic active or chronic inactive demyelinated lesions, whereas only 2 of 10 T2-only regions were demyelinated and characterized as active or chronic active lesions. Equivalent numbers of CD68⁺ leukocytes (the predominant cell type) were present in myelinated T2-only regions as compared with NAWM. Parenchymal T cells were significantly increased in T2/T1/MTR ROIs as compared with T2-only regions and NAWM. Expression of CXCR4 and phospho-CXCR4 were found on reactive microglia and macrophages in T2-only and T2/T1/MTR lesions. CXCL12 immunoreactivity was detected in astrocytes, astrocytic processes, and vascular elements in inflamed MS lesions.

Conclusions  Inflammatory leukocyte accumulation was not increased in myelinated MS ROIs with abnormal T2 signal as compared with NAWM. Robust expression of CXCR4/CXCL12 on inflammatory elements in MS lesions highlights a role of this chemokine/receptor pair in central nervous system inflammation.

Author Affiliations: Neuroinflammation Research Center (Drs Moll, Cossoy, Staugaitis, Chang, Trapp, and Ransohoff and Mss Tucky and Rietsch) and Departments of Neurosciences (Drs Moll, Cossoy, Staugaitis, Trapp, and Ransohoff and Mss Tucky, Chang, and Rietsch) and Biomedical Engineering (Dr Fisher), Lerner Research Institute, and Department of Anatomic Pathology (Dr Staugaitis), Mellen Center for Multiple Sclerosis Treatment and Research (Drs Fox and Ransohoff), Neurological Institute, Cleveland Clinic, Cleveland, Ohio. Dr Cossoy is now with the Section of Neurology, Health Science Center, and Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.

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